MXPA02001939A - Benzopyrans and benzothiopyrans as rar selective retinoid agonists. - Google Patents

Abstract

This invention relates to new RAR selective retinoid agonists of formula (I) wherein the symbols are as defined in the specification to their pharmaceutically acceptable salts, individual isomers or to a racemic or non racemic mixture; to pharmaceutical compositions containing them, and to methods for their use as therapeutic agents.

Description

RAR Selective Retinoid Agonists Description of the invention This invention relates to new selective RAR retinoid agonists, to the use of such retinoic acid receptor agonists, and in particular to selective agonists ? retinoic acid receptors (RAR? -selectives), for the treatment of emphysema. Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and death, ranked third and fourth among the leading causes of death in the European Union and in North America, respectively. COPD is characterized by a reduced maximum expiration flow, which does not change over a period of several months and which persists for 2 or more consecutive years. Patients who suffer the most severe form of COPD in general experience a significant degree of emphysema. Emphysema is defined anatomically as an enlargement of the distal permanent air space with respect to the terminal bronchioles. It is characterized by a gradual loss of pulmonary contraction, alveolar destruction, a reduction in the area of the alveolar surface and gas exchange, leading to a reduced FFU1. These two particularities, an obstruction of the gas exchange REF. : 136024 The reduction of the expiratory flow is a characteristic physiological anomaly suffered by patients with emphysema. The main symptom that is observed in patients with severe emphysema is shortness of breath when performing a minimum physical activity. The most common cause of emphysema is the habit of smoking, although other potential toxins from the environment can also contribute to this disease. These various damaging agents activate destructive processes in the lung, including the release of active proteases and free radical oxidants in excess of the protective mechanisms. The imbalance in the protease / anti-protease levels results in the destruction of the elastin matrix, the loss of elastic recoil, tissue damage and a continuous release of lung function. The elimination of harmful agents (ie, quitting smoking) slows down the rate at which damage occurs, but nevertheless, damaged alveolar structures do not recover and neither does lung function return to normal. Retinoic acid is a multi-functional modulator of cell behavior that has the potential to modify both extracellular matrix metabolism and normal epithelial differentiation. In the lung, it has been shown that acid modulates various aspects of the pulmonary differentiation by interacting with specific retinoic acid receptors (RAR) that are selectively expressed temporally and spatially. Has the coordinated activation of RARß and RAR been associated? with pulmonary branching and alveolization / septation. During alveolar septation, the granules that store retinoic acid increase in the fibroblastic mesenchyme surrounding the alveolar walls and the expression of RAR? in the lung peaks. The depletion of these retinyl ester deposits equals the deposition of a new elastin matrix and septation. As a support for this concept, Massaro and his collaborators, Am. J. Physiol., 1996, 270, L305-L310, demonstrated that the post-natal administration of retinoic acid increases the amount of alveoli in rats. Likewise, mention was made of the ability of dexamethasone to prevent the expression of CRBP and RARβ mRNA and subsequent alveolar septation in the developing lungs of rats with all-trans retinoic acid. Recent studies showed that all-trans retinoic acid can induce the formation of new alveoli and the return of elastic recoil to an almost normal level in animal models of emphysema (D. Massaro and his collaborators, Nature Medicine, 1997, 3, 675) . However, the mechanism by which this takes place remains unclear.

Retinoids are a class of compounds structurally related to vitamin A and, they comprise both natural and synthetic compounds. It has been found that several series of retinoids are clinically useful in the treatment of dermatological and oncological diseases. Retinoic acid and the other naturally occurring analogs thereof (9-cis retinoic acid, all-trans 3, 4-didehydro retinoic acid, 4-oxo retinoic acid and retinol) are pleiotropic regulatory compounds that modulate structure and function of a wide variety of inflammatory, immune and structural cells. They are important regulators of the proliferation, differentiation and morphogenesis of epithelial cells in the lungs. Retinoids have biological effects on a series of nuclear hormone receptors that are transcriptional factors that can be induced by ligands and, which belong to the super-family of steroid / thyroid receptors. The retinoid receptors are divided into two families, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), and each of these groups consists of three different subtypes (a, β, and β). Each subtype of the RAR gene family encodes a variable number of isoforms that arise from the differential division of two primary RNA transcripts. All-trans retinoic acid is the physiological hormone for retinoic acid receptors and is ligated with an almost equal affinity to all of the three RAR subtypes, but does not bind to RXR receptors, for which 9-cis acid Retinoic is the natural ligand. In many non-pulmonary tissues, retinoids have anti-inflammatory effects, modify the progression of differentiation of epithelial cells and inhibit the production of the stromal cell matrix. These properties have led to the development of therapeutic products of topical and systemic retinoids for dermatological disorders such as psoriasis, acne and hypertrophic skin wounds. Other applications include the control of acute promyelocytic leukemia, adeno-cellular and squamous cell carcinoma and hepatic fibrosis. One of the limitations in the therapeutic use of retinoids outside the cancer spectrum arose from the relative toxicity observed with naturally occurring retinoids, all-trans retinoic acid and 9-cis retinoic acid. These natural ligands are not selective and, consequently, have pleiotropic effects throughout the body that are often toxic. Recently, several retinoids have been described that interact selectively or specifically with the RAR or RXR receptors or with specific subtypes (a, ß, and?) Within a class.

In this manner, the retinoids according to the invention can also be used for the therapy and prophylaxis of dermatological disorders that are accompanied by epithelial lesions, for example acne and psoriasis. , photo-damaged and aged skin, as well as for the promotion of wound healing, for example incision wounds such as surgical wounds, wounds that cause burns and other wounds caused by skin trauma; and for the therapy and prophylaxis of malignant and premalignant epithelial lesions, tumors and pre-cancerous changes of the mucous membrane in the mouth, tongue, larynx, esophagus, bladder, neck and colon. This invention provides new selective RAR retinoid agonists of the formula I wherein R1 is hydrogen, lower alkyl; R2 is lower alkyl; R3 is lower alkyl or H; X is oxygen or sulfur; n is 1 or 2; and where the dotted line link is optional; and the pharmaceutically active salts of the carboxylic acids of the formula I. The compounds of the formula I can be present in the form of a racemic mixture, i.e., 5- (RS) or in the pure enantiomeric form as an isomer 5- (S) or 5 (R). When the point link is present, a triple link is referenced, in cases, where the point link is absent, to a double link.

In cases where the "dotted line link" is absent, the double link may have an "E" or "Z" configuration. The terms "E" and "Z" are used herein as defined in Puré and Applied Chem., 1976, 54, 12. The term "lower alkyl", as used herein, refers to straight or branched chain alkyl residues containing between 1 and 5 carbon atoms, such as, for example, methyl, ethyl, propyl. , isopropyl, butyl, isobutyl, tert-butyl, pentyl, amyl and 3-pentyl. The compounds of the formula I, in which R 1 is hydrogen, form a salt with pharmaceutically acceptable salts such as the alkali salts, for example, Id A &AMALI. salts of Na and K, and with the ammonium or substituted ammonium salts such as the trimethylammonium salts, which are within the scope of the present invention. Preferred compounds of the formula I are the compounds of the formula IA: where: X, R1, R2, R3, n and the dotted line bond are as defined above; and the pharmaceutically active salts of the carboxylic acids of the formula IA. In particular, the compounds of the formula IA that are preferred are the compounds in which X is oxygen and n is 2 and, in particular, the compounds: A. 4- (5-methoxymethyl-5-methyl-2,3 acid, 4, 5-tetrahydro-l-benzo [b] oxepin-8-yl-ethynyl) -benzoic acid B. 4- (5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] oxepin- 8-ylethynyl) -benzoic acid C. 4- (5-methyl-5-propoxymethyl-2, 3, 4, 5-tetrahydro) Benzo [b] oxepin-8-ylethynyl) -benzoic acid D. (E) -4- [2- (5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo [b] oxepin-8-yl) acid ) -vinyl] -benzoic acid E. (E) -4- [2- (5-methoxymethyl-5-methyl-2, 3, 4, 5, 5-tetrahydrobenzo [b] oxepin-8-yl) -vinyl] - benzoic acid F. (E) -4- [2- (5-methyl-5-propoxymethyl-2,3,4,5-tetrahydrobenzo [b] oxepin-8-yl) -vinyl] -benzoic acid. Other compounds that are especially preferred are the compounds of the formula IA, where X is sulfur and n is 2 and, in particular, the compounds: G. 4- (5-methoxymethyl-5-methyl-2, 3, 5 -tetrahydrobenzo [b] thiepin-8-ylethynyl) -benzoic acid H. 4- (5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydro-15-benzo [b] thiepin-8-ylethynyl) -benzoic acid I. (E) -4- [2- (5-Ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepin-8-yl) -vinyl] -benzoic acid acid (E) ) -4- [2- (5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo [b] thiepin-8-yl) -vinyl] -benzoic acid. Another group of compounds that is preferred is given by the compounds of the formula IB: 4-where X, R1, R2, R3, n and the dotted line bond are as defined above; and the pharmaceutically active salts of the carboxylic acids of the formula IB. Especially preferred compounds of the formula IB are those in which n is 1 and X is oxygen, such as, for example, the compounds: K. 4- (4-methoxymethyl-4-methyl-chroman-6-ylethynyl acid) -benzoic acid L. (E) -4- [2- (4-methoxymethyl-4-methyl-chroman-6-yl) vinyl] -benzoic acid. The compounds according to the invention can be prepared in a manner known in the art. The compounds of the formula IA, in which n is 2 y, in which the dotted line bond is present can be prepared according to the method presented in Reaction scheme 1. i l iiii? * ?, »M * ÁA. where the dotted line is present, and where the symbols are as defined above and, where Hal is halogen as, for example, iodine, bromine or chlorine.

Reaction step la: A dihydrobenzo [b] oxepin or a dihydrobenzo [b] thiepinone-1 (1) is subjected to a Wittig reaction with (methoxymethyl) triphenylphosphonium chloride to form, after acid hydrolysis, the aldehyde (2). ), the reaction is preferably carried out in a solvent such as, for example, ; fc 1"Í-Í. tetrahydrofuran (THF) example, at temperatures between -78 ° C and 0 ° C approximately.

Reaction step lb: Subsequently, the carbaldehyde is alkylated to form (3) with a suitable alkylhalide, preferably an alkyldide, in the presence of a base such as, for example, potassium ter-butylate in a polar solvent and, preferably, in a -butanol. The 0-alkylated by-products can be separated and recycled if desired.

Reaction step lc: Preferably, the reduction of the alkylated carbaldehyde (3) is carried out with sodium borohydride. The primary alcohol (4) obtained by this reduction is subjected to step Id.

Reaction step Id: This etherification is preferably carried out by deprotonation with a strong base such as, for example, sodium hydride which is a polar solvent and, preferably, N, N-dimethylformamide (DMF) and, by subsequent alkylation with an alkylhalide and, preferably, an alkyldide.

.Jiji. J.Jk A * .Í..k.

Reaction steps le, lf and Ig: Tetrahydro-oxepine or halogenated thiepin is coupled (5) with trimethylsilylacetylene in the presence of a base such as, for example, piperidine or triethylamine and catalytic amounts of Cul, triphenylphosphine and bis chloride (triphenylphosphine) palladium (II) or tetracis- (triphenylphosphine) -palladium (0) to form the ethynylated derivative (6) (reaction step le). After desilylation with catalytic amounts of sodium methylate in methanol to form the compound (7) (reaction step lf), the alkyl-4-iodo-benzoate is bound by a second coupling of Sonogashira in the presence of a base such as triethylamine and, of catalytic amounts of copper iodide, triphenylphosphine and bis (triphenylphosphine) chloride palladium (II) to obtain the compound IA, in n is 2.

Reaction step lh: In the alternative brief method, it is possible to directly react the tetrahydro-oxepine and halogenated-thiepne, respectively, (5) with alkyl (4-ethynyl) benzoate, as described in the reaction step , in the presence of Cul, triphenylphosphine and tetracis- (triphenylphosphine) palladium (0) or bis- (triphenylphosphine) palladium (II) chloride to obtain compound IA. li fciá »fc. * - UkA * A mZ I *. However, if Hal is Br, the results are satisfactory only in the sulfur series. The compounds of formula IA, in which the dotted line bond is absent, can be prepared according to the method presented in Reaction Scheme 2.

Reaction scheme 2 where the dotted line link is absent, and where the symbols are as defined above.

Reaction step 2a: Subsequently, the tetrahydro-oxepine or halogenated -thiepine is reacted, respectively, (5) with butyllithium and dimethyl formamide at -78 ° C to obtain, after Í? The work procedure is carried out with ammonium chloride, the desired aldehyde (8).

Reaction step 2b: Thereafter, the aldehyde (8) is further elaborated by means of a Wittig-Horner reaction with the appropriate benzylic phosphonate in a polar aprotic solvent, preferably N, N-dimethylformamide or dimethylsulfoxide, in presence of a strong base, for example sodium hydride, to obtain the trans-olefin (9). The compounds of formula IB, wherein n is 1 or 2, could be prepared according to the methods depicted in reaction schemes 3 and 4.

"Reaction scheme 3 where the dotted line is present, and where the symbols are as defined above.

Reaction scheme 4 "where the dotted line is absent, and where the symbols are as defined above, although the compounds of formula IA can be prepared from the meta-halogenated compounds (1), which are readily available and which they are marketed as m-bromo-phenol and m-bromo-thiophenol, respectively, the compounds of the formula IB are prepared from the non-halogenated compounds (10), (prepared from phenol and thiophenol, respectively) and which are functionalized at a later stage following conventional halogenation methods, see reaction step 3d. If R3 = H in the compounds of formulas IA and IB, then the primary hydroxy group, such as acetate, should be adequately protected throughout the synthesis. Finally, the ester group COOR1 of the compounds of the formula IA and IB can be hydrolysed to form the free acids according to standard conditions as, for example, with sodium hydride in THF / ethanol / acetone. In another aspect, this invention relates to the use of a selective RAR agonist where systemic administration is a mode of administration that is preferred for the treatment of emphysema and associated pulmonary diseases. Thus, it relates to a method for the treatment of emphysema and associated lung diseases through the treatment of a mammal with a selective RAR agonist, where systemic administration is a mode of administration that is preferred. A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for the treatment or prevention of a disease, is sufficient to effect such treatment or prevention of the disease. The "therapeutically effective amount" will vary according to the compound, the disease and its severity as well as according to the age, weight, etc., of the mammal to be treated. The selectivity of the RAR agonist? of a compound can be determined by routine ligand binding assays that are known to all those skilled in the art, such as those described in C. Apfel et al., Proc. Nat. Sci. Acad. (USA), 89: 7129-7133 (199 ?.); M. Teng et al., J. Med. Chem., 90: 2445-2451 (1997); and in PCT Publication WO 96/30009. The use of the RAR agonists disclosed herein can be used to promote repair of damaged alveoli and septation of new alveoli and, in particular, for the treatment of emphysema. Treatment with RAR agonists and, in particular with selective RAR? Agonists, is useful to promote repair of the alveolar matrix and septation. As such, the methods that are ? dxk iáj¡i.? i f ¡v «He reported in the present are useful for the treatment of diseases such as emphysema. In general, the dosage will vary between 0.01 and 1.0 mg / kg of body weight approximately per day and, preferably, between 0.05 and 0.5 mg / kg of body weight approximately per day. In particular, the dosage of a selective RAR agonist necessary to treat lung emphysema will depend on the severity of the condition. This dosage may be administered in a conventional pharmaceutical composition by a single administration, by multiple applications or by controlled release, as necessary to achieve the most effective results. The dosage will continue for as long as clinically indicated, which according to the severity of the disease, may range from a few weeks to several months. Generally, a pharmaceutically acceptable composition, for example a salt, of the RAR agonist of the formula I is administered in a pharmaceutically acceptable carrier or diluent. Within the context of the present invention, pharmaceutically acceptable salts include any chemically suitable salt known in the art of retinoid agonists, as applicable for administration to human patients. Examples of conventional salts known in the art include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts and ammonium and alkyl ammonium salts. Representative administration regimens include oral, parenteral (including subcutaneous, intramuscular, and intravenous), rectal, buccal (including sublingual), transdermal, pulmonary, and intranasal administration. A method of pulmonary administration comprises the aerosolization of an aqueous solution of a RAR agonist. The aerosolized compositions can include the compound packaged in micelles or reverse liposomes. Typical pulmonary and respiratory delivery systems are described in U.S. Patents. Nos. 5,607,915, 5,238,683, 5,292,499 and 5,364, 615. The methods of treatment of the present invention also include the systemic administration of RAR agonists in a simultaneous or sequential combination with another active ingredient. In general, RAR agonists will be administered in the form of pharmaceutical compositions in admixture with a pharmaceutically acceptable, non-toxic carrier. As mentioned above, such compositions can be prepared for parenteral administration (subcutaneous, . J .., ti, Ja, Ífifiati, ..., _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _, in particular in the form of liquid solutions or suspension; for oral or buccal administration, in particular in the form of tablets or capsules; for intranasal administration, in particular in the form of powders, nasal drops or aerosols; and for rectal or transdermal administration. Any conventional vehicle material can be used. The carrier material may be any organic or inorganic carrier, for example water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, polyalkylene glycols, petroleum jelly and the like. Liquid formulations for parenteral administration may contain as excipients water or sterile saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Various slightly acidic buffer solutions can be employed at pH ranges between about 9 and about 6. Suitable buffers include acetate, ascorbate and citrate at concentrations ranging from about 5 mM to about 50 mM. For oral administration, the formulation can be optimized by the addition of bile salts or acylcarnitines. fl? «i > A * Hrr'f? * * * - «* - ** ^ f The formulations for nasal administration may be solid and may contain excipients, for example lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or sprays measured. Nasal formulations in particular include dry powders suitable for conventional dry powder inhalers (DPIs), liquid solutions or suspensions suitable for nebulization, and propellant formulations suitable for use in metered dose inhalers (MDI). For buccal administration, typical excipients include sugars, calcium stearate, magnesium stearate, pre-gelatinized starch and the like. When formulated for nasal administration, absorption by the nasal mucous membrane can be enhanced with surfactant acids such as, for example, glycocholic acid, cholic acid, taurocholic acid, ethocolic acid, deoxycholic acid, chenodeoxycholic acid, dehydrocholic acid, glycodeoxycholic acid, cyclodextrins. and the like in an amount of from about 0.2 to 15 weight percent, and preferably from about 0.5 to 4 weight percent, and more preferably from about 2 weight percent. Solid forms for oral administration include tablets, hard and soft gelatin capsules, pills and YES-A t .. pills, powders, granules and other similar. Each tablet, pill or pill can contain between 1 and 50 mg approximately and, preferably, between 5 and 10 mg approximately of RAR agonists. Preferred solid dosage forms for oral administration include tablets, hard-coated two-part capsules and soft elastic gelatin capsules (SEG). The SEG capsules are of particular interest because they provide differentiated advantages over the other two forms (see Seager, H., "Soft gelatin capsules: a solution to many tableting problems", Pharmaceutical Technolgy, 9, (1985)). . Some of the advantages associated with the use of SEG capsules are: a) the dose-content uniformity in SEG capsules is optimized because the drug dissolves or disperses in a liquid that can be dosed inside the capsules; in a precise way; b) Drugs formulated as SEG capsules have a good bioavailability because the drug dissolves, solubilizes or disperses in a miscible aqueous liquid or in an oily liquid and, therefore, when released into the body, the solutions are they dissolve or emulsify in order to produce dispersions of the drug with a large surface area and c) the degradation of drugs that are sensitive to oxidation during long-term storage due to the dry coating is prevented. mmmríkailt ¿-fe¿ i. l. mr * ¿-émZ. ,. . . , -i.A. t.

The administration of the compounds of the present invention to a person for prolonged periods, for example, for periods ranging from one week to one year, can be carried out in a single administration of a controlled release system containing the sufficient ingredient. active for the controlled release period. Various controlled release systems can be used such as monolithic or reservoir type microcapsules, reservoir implants, osmotic pumps, vesicles, micelles, liposomes, traasdermic patches, iontophoretic devices and alternative injectable dosage forms for this purpose. The location at the site where said administration of the active ingredient is desired is an additional feature of some of the controlled release devices, which may be beneficial in the treatment of certain disorders. Those included below are representative pharmaceutical formulations for the use of selective RAR agonists as described herein, the purpose of which is to promote repair of the elastin-mediated matrix and alveolar septation. The preparations and examples that follow are given in order to allow all those skilled in the art to better understand and be able to practice the present invention. Consequently, it should not be considered as limiting the scope of the invention but merely as illustrative and representative of it.

Tablet formulation The ingredients detailed below were mixed very well and compressed into single tablets.

Amount per ingredient Tablet, mg RAR agonist of the formula I 10 Corn starch 50 Croscarmellose sodium 25 Lactose 120 Magnesium stearate 5 Capsule Formulation The ingredients detailed below were thoroughly mixed and filled into a hard shell gelatin capsule.

Suspension formulation The following ingredients were mixed to form a suspension for oral administration.

Injectable formulation The ingredients that are included below were mixed in order to form an injectable formulation.

Nasal formulation The ingredients below were mixed in order to form a suspension for nasal administration.

The compounds prepared in the examples given below were prepared as racemic mixtures. However, racemic mixtures can be easily resolved in the respective enantiomers following well-established methods such as, for example, ?TO? aMm? rummí, - "---" "• -.,» - ». ^ ¿. ..- * .... ¿Mlrí. TO.. 2, 3, 4, 5-tetrahydrobenzo [b] oxepinyl-methanol or 2,3,4,5-tetrahydrobenzo [b] tiepini-methanol, respectively. Such methods include separation by HPLC on a chiral column, for example a chiral column NUCLEOSIL; or separation by derivatization with a chiral acid such as, for example, Mosher's acid, or separation of the corresponding diastereomers following conventional techniques followed by reductive or hydrolytic cleavage of the ester.

Example 1 1.1. Preparation of 4- (5-methoxymethyl-5-methyl-2, 3, 4, 5-tetrahydrobenzo [b] oxepin-8-ylethynyl) -benzoic acid a] 8-Bromo-2, 3, 4, 5-tetrahydrobenzo [b] oxepin-5-carbaldehyde 14.27 g (1.6 eq.) of sodium chloride were suspended. (methoxymethyl) triphenylphosphine in 50 ml of abs. THF. and was deprotonated at a temperature of -10 ° C and -5 ° C by the ltí ??.?. * m, aA *? ..., added by means of a syringe of 25.2 ml of 1.6 M n-butyl-lithium (1.55 eq., in hexane). The resulting red ylide solution was cooled to -75 ° C and treated with 6.20 g (26.0 mmol) of 8-bromo-3,4-dihydro-2H-benzo [b] oxepin-5-one dissolved in 13 ml of THF abs. After that, the mixture was kept for 0.2 h at -78 ° C and for 1 h at room temperature, then poured into crushed ice and extracted with diethyl ether. The organic phase was washed with water and dried over magnesium sulfate, then filtered and the solvent evaporated to obtain a crude product to which it was purified by flash chromatography (SiO2, hexane / ethyl acetate = 95/5). Consequently, 5.85 g of 8-bromo-5-methoxymethylene-2,3,4,5-tetrahydrobenzo [b] oxepin was obtained in the form of an E / Z mixture to which it was hydrolyzed in the following manner: this enol ether (21.7 mmol) in 30 ml of THF and then treated with 31.5 ml of 35% HC104. After stirring for 16 h, the resulting mixture was distributed between water and the temperature of the ice and diethyl ether. The organic layer was washed with Na 2 CO 3 (pH ca.10) and water, dried over magnesium sulfate, then filtered and the solvent was evaporated to obtain 4.63 g of the title compound in the form of a colorless oil (neat in a 96% according to GC (gas chromatography)). bj 8-Bromo-5-methyl-2, 3, 4, 5-tetrahydrobenzo [b] oxepin-5-carbaldehyde 2.59 g (10.2 mmol) of 8-bromo-2,3,4,5-tetrahydrobenzo [b] was dissolved. ] oxepin-5-carbaldehyde in 25 ml of tert-butanol abs. At 0 ° C, 2.28 g (2 eq.) Of potassium tert-butylate was introduced, followed by 1.58 ml (2.5 eq.) Of methyliodide after 0.3 h. stirring was continued at room temperature until TLC (thin layer chromatography) indicated the disappearance of the initial material. After that, the reaction mixture was poured onto crushed ice and extracted twice with diethyl ether. The organic phase was washed with water, dried over magnesium sulfate, filtered and, subsequently, the solvent was evaporated under reduced pressure. Flash chromatography (Si02, hexane / ethyl acetate 97/3) allowed to obtain 1.85 g of the title compound in the form of a colorless oil (98% pure according to GC). c] (8-Bromo-5-methyl-2, 3, 4, 5-tetrahydrobenzo [b] oxepin-5-yl) -methanol 20.6 g (76.5 mmol) of 8-bromo-5-methyl-2 were dissolved, 3, 4, 5-tetrahydrobenzo [b] oxepin-5-carbaldehyde in 100 ml of abs. Ethanol. and cooled to 0 ° C. 2.896 g (1 mol eq.) Of NaBH4 were introduced in several portions and the reaction was allowed to proceed for 0.5 h at 0 ° C and, for 0.5 h at room temperature. After that, the reaction mixture was poured onto crushed ice and extracted with diethyl ether. The organic phase was washed with water, dried over sodium sulfate and then the solvent was evaporated. Accordingly, 21.5 g of the title compound was obtained in the form of a colorless oil, pure enough to proceed to the next step. d] 8-Bromo-5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] oxepine The primary alcohol obtained above (76.5 mmol) was dissolved in 100 ml of abs. DMF. and treated at -10 ° C with 2.40 g of NaH (ca. 50% in mineral oil, ca 1.3 eq.). The deprotonation was allowed to take place at room temperature. Once evolution of hydrogen ceased, the mixture was cooled to 0 ° C, treated with 6.24 ml of methyloduro (1.3 eq.) And then maintained for 0.2 h at 0 ° C and for 0.75 h at room temperature (an white precipitate of Nal). Hydrolysis with cold water, extraction with diethyl ether, washing of the organic phase with a solution of NH4C1, drying in sodium sulfate, filtering and finally evaporation of the solvent allowed to obtain a crude product, which was purified by filtration. in Si02, (hexane / ethyl acetate, 95/5) to obtain 22.5 g of the title product in the form of a colorless oil (96.5% pure according to GC). e] (5-Methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] oxepin-8-ylethynyl) -trimethylsilane A 22.5 g (< 76.5 mmol) of 8-bromo-5-methoxymethyl-5 -methyl 2, 3, 4, 5-tetrahydro-benzo [b] oxepin, dissolved in 50 ml of piperidine, were introduced, in succession, 291 mg (0.02 eq.) of Cul, 401 mg (0.02 eq.) of triphenylphosphine (Ph3P), and 884 mg (0.01 eq.) of (Ph3P) 4Pd. After heating to 80 ° C, a solution of 26.5 ml (2.5 eq.) Of trimethylsilylacetylene in 25 ml of piperidine was introduced in 1 h through a dropping funnel. Since the GC analysis indicated that 6% of the starting material still remained, an additional 3 ml of trimethylsilylacetylene was added in two portions. After cooling, the reaction mixture was poured onto crushed ice, extracted with diethyl ether, the organic phase was washed with dil. HCl, dried over sodium sulfate, and then filtered and evaporated to dryness. Flash chromatography (Si02, hexane / ethyl acetate 95/5) allowed to obtain 26.3 g of the title compound in the form of a yellowish oil, pure enough to pass to the next step (91% pure according to GC ) r «? * 9_ foJÁ ait1-" * • fj 8-Ethynyl-5-methoxymethyl-5-methyl-2, 3, 4, 5-tetrahydrobenzo [b] oxepin A small part of sodium was dissolved in 100 ml of abs. methanol. The sodium methylate solution was introduced in one portion in 26.3 g (< 76 mmol) of 5-methoxymethyl-5-methyl-2, 3, 4, 5-tetrahydrobenzo [b] oxepin-8-ylethynyl) -trimethylsilane prepared before at 0 ° C and then maintained for 0.75 h at room temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and then extracted with diethyl ether, the organic phase was separated, dried over sodium sulfate, filtered and the solvents were subsequently removed. Flash chromatography (Si02, hexane / ethyl acetate 96/9) allowed to obtain 15.60 g of the title compound in the form of a pale yellow oil (96.5% pure according to GC). g] 4- (5-Methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] oxepin-8-ylethynyl) -benzoic acid methyl ester In 165 ml of DMF abs. were dissolved, successively, 20.96 g (1.25 eq.) of methyl 4-iodobenzoate, 2.29 g (0.04 eq.) of bis (triphenylphosphine) palladium (II) chloride, 1.86 g (0.12 eq.) of Cul and 27.9 ml (2.5 eq.) of triethylamine. 19.67 g (63.7 mmol) of the 8-ethynyl-5-methoxymethyl-5-methyl-2, 3,4,5-tetrahydrobenzo [b] oxepin prepared above, dissolved in 60 ml of abs. DMF, were introduced in 0.75 ha. through a dropping funnel, and 0.25 h later, the reaction was warmed by pouring the reaction mixture onto crushed ice / HCl, extracted with diethylether; the organic phase was washed with water, dried over sodium sulfate, filtered and evaporated to dryness. Flash chromatography (SiO2, hexane / ethyl acetate, 91/9) allowed to produce, after crystallization from the same solvent mixture, 19.5 g of the title compound in the form of white crystals with a m.p. of 111.5-112.5 ° C. h] 4- (5-Methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] oxepin-8-ylethynyl) -benzoic acid 20.06 g (55.04 mmol) of methyl ester of 4- ( 5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] -oxepin-8-ylethynyl) -benzoic acid in 100 ml of THF / ethanol (1/1) and treated with 8.81 g (4 eq. .) of NaOH, dissolved in 50 ml of water. The reaction bottle was kept in the dark and stirring was continued for 42 h at room temperature. After that, the mixture was poured onto crushed ice / 60 ml of 25% HCl, extracted twice with ethyl acetate; the organic phase was washed with a small amount of water, dried over sodium sulfate, filtered and then evaporated to dryness. The ÍÍÍ.A?, Í & rl í.ite ± aé .. crystallization from hexane / ethyl acetate allowed 18.90 g of the title product to be obtained in the form of pale yellow crystals with a m.p. of 205-206 ° C.

Elemental analysis: C22H2204 Calculated: C 75.41% H 6.33% Observed: C 75.31% H 6.17%.

NMR: (1H, d, TMS, CDC13) 1.40 (s, 3H), 1.59 (m, 1H), 1.9-2.15 (m, 3H), 3.36 (s, 3H), 3.37 (d, J = 9, 1H ), 3.83 (d, J = 9, 1H), 3.85 (m, 1H), 4.10 (m, 1H), 7.18 (d, J = 1, 1H), 7.23 (dxd, J = 8, J = 1, 1H), 7.28 (d, J = 8, 1H), 7.60 (d, J = 8. 5, 2H), 8.09 (d, J = 8.5, 2H). 1. 2. Preparation of 4- (5-ethoxymethyl-5-methyl-2, 3, 4, 5-tetrahydrobenzo [b] oxepin-8-ylethynyl) -benzoic acid This compound was prepared in a manner analogous to that of Example 1.1. but using ethyliodide in step d] instead of using methyloduro. Crystals were obtained whites with a p.f. from 170-171 ° C. MS: (M) + 364, (M-CH2OC2H5) + 305. 1. 3. Preparation of 4- (5-methyl-5-propoxymethyl-2, 3, 4, 5-tetrahydrobenzo [b] oxepin-8-ylethynyl) -benzoic acid This compound was prepared in a manner analogous to that of Example 1.1. but using propyl iodide in step d] instead of using methyl iodide. Ivory crystals with a m.p. of 148-149 ° C. MS: (M) + 378, (M-CH2OC3H7) + 305.

Example 2 2.1. Preparation of 4- [2- (5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo [b] oxepin-8-yl) -vinyl] -benzoic acid tá¿¿ »aasi * - aj 5-Allyl-8-bromo-2,3,4,5-tetrahydrobenzo [b] oxepin-5-carbaldehyde 0.55 g (2.18 mmol) of 8-bromo-2,3,4,5-tetrahydrobenzo [b were dissolved ] oxepin-5-carbaldehyde (see Example 1, step a)) in 5 ml of abs. THF. and 1 ml of tert-butanol abs. At 0 ° C, 0.490 g (2 eq.) Of potassium tert-butylate was introduced, followed by 0.552 ml (3 eq.) Of allylbromide after 0.1 h. Stirring was continued at the same temperature until the TLC (thin layer chromatography) indicated the disappearance of the initial material. After that, the reaction mixture was poured onto crushed ice / NH 4 Cl solution, extracted twice with diethyl ether, the organic phase was washed with water, dried over sodium sulfate, filtered and finally the solvents were removed. Flash chromatography (Si02, hexane / ethyl acetate 95/5) allowed to obtain 0.224 g of the title compound in the form of a colorless oil (98% pure according to GC). bj (5-Allyl-8-bromo-2,3,4,5-tetrahydrobenzo [b] oxepin-5-yl) -methanol 0.216 g (0.732 mmol) of 5-allyl-8-bromo-2,3 were dissolved , 4,5-tetrahydrobenzo [b] oxepin-5-carbaldehyde in 7 ml of abs. Ethanol. and cooled to 0 ° C. Immediately, 0.028 g (1 mol-eq.) Of NaBH4 were introduced and the reaction was allowed to continue for 0.5 h at 0 ° C. The poured on crushed ice, the extraction - twice - with diethyl ether, the washing of the organic phase with water and the drying in sodium sulfate, the subsequent filtering and the elimination of the solvent allowed to obtain 0.230 g of the title compound in the form of a colorless oil, pure enough to pass to the next step (96% pure according to GC). c] (8-Bromo-5-propyl-2, 3, 4, 5-tetrahydrobenzo [b] oxepin-5-yl) -methanol 0.230 g of (5-allyl-8-bromo-2, 3, 4 , 5-tetrahydrobenzo [b] oxepin-5-yl) -methanol which was prepared before in 10 ml of ethyl acetate and hydrogenated in 0.20 g of Pd / C, 5%, for 0.5 h at room temperature and 1 atm (l.OlxlO5 Pa) of H2. The progress of the reaction should be carefully monitored in order to avoid bromine reduction removal. After filtration through a pad of Celite, the solvent was removed. The u A? m. l-? t j.S,: í. flash chromatography (Si02, hexane / ethyl acetate 8/2) allowed to produce 0.191 g of the title compound in the form of a colorless oil (GC - purity 91%). In principle, this intermediary can also be prepared in accordance with what is described in the Example 1, step b) by the use of propyl iodide for the alkylation. Nevertheless, the yields are notably lower. dj 8-Bromo-5-methoxymethyl-5-propyl-2, 3,4,5-tetrahydrobenzo [b] oxepine 0.191 g (0.638 mmol) of (8-bromo-5-propyl-2, 3, 4, 5-tetrahydrobenzo [b] oxepin-5-yl) -methanol) in 3 ml of DMF abs. and treated at 0 ° C with 0.061 g of NaH (ca., 50% in mineral oil, ca. 2 eq.). The deprotonation was allowed to take place at room temperature for 0.2 h. The mixture was cooled to 0 ° C and treated with 0.079 ml of methyl iodide (2 eq.) And then kept for 1 hour at room temperature. Hydrolysis with cold water, acidification with a solution of NHC1, extraction with diethyl ether, drying of the organic phase in sodium sulfate, filtration and evaporation of the solvents allowed to obtain a crude product to which it was purified by flash chromatography. (Si02, hexane / ethyl acetate 96/4) to obtain 0.179 g of the title compound in Í? Kíé, árá ^ .iuáí ^ ^,? Ím »? I * the form of a colorless oil (93% pure according to GC). e] 5-Methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo [b] oxepin-8-carbaldehyde 0.179 g (0.571 mmol) of 8-bromo-5-methoxymethyl-5-propyl-2 were dissolved, 3, 4, 5-tetrahydrobenzo [b] oxepin in 5 ml of THF abs. and cooled to -78 ° C. 0.447 ml of n-butyllithium (1.5M, hexane) was slowly added and the temperature was maintained for 0.2 h. Then 0.141 ml (3.2 eq.) Of abs. DMF was introduced. with a syringe and stirring continued for 0.25 h. Tempering at room temperature, pouring on crushed ice / NH4C1 solution, extraction - twice - with diethyl ether and drying the organic phase in sodium sulphate, filtering and evaporating the solvent allowed to obtain 0.18 g of a product crude, which was purified by flash chromatography (Si02, hexane / ethyl acetate 9/1) to obtain 0.125 g of the title compound in the form of a colorless oil (98% pure according to CC). f] Ethyl ester of (E) -4- [2- (5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo [b] oxepin-8-yl) -vinyl] -benzoic acid 0.048 g of NaH (50% in mineral oil) were suspended in 3 ml of DMF abs. Then, 0.27 g of 4- (diethoxyphosphorylmethyl) -benzoic acid ethyl ester was introduced at 0 ° C. The mixture was stirred at room temperature until the formation of H2 ceased. After cooling to -10 ° C, 0.119 g (0.954 mmol) of 5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo [b] oxepin-8-carbaldehyde, dissolved in 2 ml of DMF, was introduced. , and the reaction was allowed to take place for 0.2 h at -10 ° C and then for 1 h at room temperature. After that, the mixture was poured onto crushed ice / NHC1 solution, extracted with diethyl ether, the organic phase was washed with water, dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by flash chromatography (silica gel, hexane / ethyl acetate 9/1) finally allowed to obtain 0.088 g of the pure, colorless title compound, which solidified spontaneously. g] 4- [2- (5-Methoxymethyl-5-propyl-2, 3,4,5-tetrahydrobenzo [b] oxepin-8-yl) -vinyl] -benzoic acid 0.081 g (0.198 mmol) of acid was dissolved (E) -4- [2- (5-methoxymethyl-5-propyl-2, 3,, 5-tetrahydrobenzo [b] oxepin-8-yl) vinyl] -benzoic acid ethyl ester in 1 ml of THF / ethanol (1/1) and treated with 0.33 ml of 3N NaOH (5 eq). The reaction flask was kept in the dark and continued stirring for 20 h at room temperature. Afterwards, the mixture was poured onto crushed ice / dilute HCl, extracted twice with ethyl acetate, the organic phase was washed with water, dried over sodium sulfate, filtered and evaporated to dryness. Crystallization from hexane / ethyl acetate allowed 0.46 g of the title product to be obtained in the form of white crystals with a m.p. from 157-159 ° C. MS: (M) + 380, (M-CH2OCH3) + 335. NMR: (1H, d, TMS, DMSO) 0.81 (t, J = 7, 3H), 0.9-1.25 (m, 2H), 1.6-2.05 (, 6H), 3.30 (s, 3H), 3.44 (d, J = 9, 1H), 3.66 (d, J = 9, 1H), 3.72 (m, 1H), 4.11 (m, 1H), 7.17 ( d, J = 8, 1H), 7.21 (d, J = 1, 1H), 7.28 (dxt, J = 8, J = 1, 1H), 7.31 (br s, 2H), 7.70 (d, J = 8 , 2H), 7.93 (d, J = 8, 2H), 12.91 (br s, COOH). 2. 2. Preparation of (E) -4- [2- (5-methoxymethyl-5-methyl-2,3,4,5-tetrahydro-benzo [b] oxepin-8-yl) -vinyl] -benzoic acid This compound was prepared in a manner analogous to that of Example 2.1, but instead of 8-bromo-5-methoxymethyl-5- methyl-2, 3, 4, 5-tetrahydrobenzo [b] oxepin, the propyl analog was used in step e]. Colorless crystals with a m.p. of 199-96 ° C. CI-MS: (MH) + 351. IR (cm_1): 2667, 2546, 1688, 1606, 1567, 1419, 1291, 1238, 1179, 1080, 958, 871, 768. NMR: (1H, d, TMS, CDC13) 1.41 (s, 3H), 1.59 (m, 1H), 1.92- 2.15 (m, 3H), 3.37 (s, 3H), 3.37 (d, J = 9, 1H), 3.84 (d, J = 9 , 1H), 3.86 (m, 1H), 4.12 (m, 1H), 7.08-7.28 (m, 5H), 7.58 (d, J = 8.2, 2H), 8.09 (d, J = 8.2, 2H). 2.3. Preparation of (E) -4- [2- (5-methyl-5-propoxymethyl-2,3,4,5-tetrahydrobenzo [b] oxepin-8-l) -vinyl] -benzoic acid It was prepared in a manner analogous to that of Example 2.1, but, in step e] 8-bromo-5-methyl-5-propoxymethyl-2,3,4,5-tetrahydrobenzo [b] oxepma was used instead of use 8-bromo-5-methoxymethyl-5-propyl-2, 3,4,5-tetrahydrobenzo [b] oxepin. Colorless crystals with a m.p. from 164-65 ° C. Í. &ri? rá.ik .i *? á¿Á .... 3 & amp; ¿?? ~mmr ~. .

MS: (M) + 380, (M-CH2OC3H7) + 307. 2. 4. Preparation of (E) -4- [2- (4-methoxymethyl-4-methyl-chroman-6-yl) -vinyl] -benzoic acid It was prepared in a manner analogous to that of Example 2.1, but instead of 8-bromo-5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo [b] oxepine it was used in step e] -bromo-4-methoxymethyl-4-methyl-chroman, whose synthesis is described in Example 5 d]. Crystals with a yellowish color and with a p.f. of 209-210 ° C.

NMR: (1H, d, TMS, DMSO) 1.30 (s, 3H), 1.68 (dxdxd, 1H), 2.04 dxdxd, 1H), 3.27 (s, 3H), 3.41 (d, J = 9.1H), 3.51 ( d, J = 9.1H), 9.17 (m, 2H), 6.77 (d, J = 8.1H), 7.18 (d, J = 16.1H), 7.32 (d, J = 16.1H), 7.38 (dxd, J = 8, J = 2.1H), 7.60 (d, J = 2.1H), 7.66 (d, J = 8.3, 2H), 7.91 (d, J = 8.3, 2H). lütAA. A > - • ***** - '- - ~ & J & & amp; & amp; Í Jtt ^ j. A ^ fa, & ^ Í.

CI-MS: (M-H) + 337.

Example 3 3.1. Preparation of 4- (5-methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepin-8-ylethynyl) -benzoic acid a] 8-Bromo-2,3,4,5-tetrahydrobenzo [b] thiepin-5-carbaldehyde 16.68 g (1.6 eq.) of (methoxymethyl) triphenylphosphonium chloride were suspended in 75 ml of abs. THF. and was deprotonated between -15 ° C and -5 ° C by adding with a syringe of 29.5 ml of 1.6 M n-butyllithium (hexane, 1.55 eq.). The resulting red ylide solution was cooled to -75 ° C and treated with 7.82 g (30.9 mmol) of 8-bromo-3,4-dihydro-2H-benzo [b] tiepin-5-one, dissolved in 15 ml. of THF abs. The mixture was then kept for 0.3 h at -78 ° C and, subsequently, for 1.25 h at room temperature. The pouring on crushed ice, the extraction - twice - with diethyl ether, the washing of the organic phase with water, the After drying in magnesium sulfate, filtering and evaporating the solvents allowed a crude product to be obtained, which was purified by flash chromatography (SiO2, hexane / ethyl acetate, 95/5), so that 7.39 g of 8-bromo-5-methoxymethylene-2 were obtained, 3, 5-tetrahydrobenzo [b] thiepine in the form of an E / Z mixture to which it was hydrolyzed in the following way: This enol ether (25.8 mmol) was dissolved in 37 ml of THF and subsequently treated with 37 ml of HC104 at 35%. After stirring for 16 h at room temperature, the resulting mixture was distributed between cold water such as ice and diethyl ether, the organic layer was washed twice with Na 2 CO 3 (pH ca.10) and water, dried over magnesium sulfate, filtered and then evaporated to dryness. Purification of the residue by flash chromatography (silica gel, hexane / ethyl acetate, 95/5) finally allowed 6.33 g of the title compound to be obtained in the form of a colorless oil (98% pure according to GC). MS: (M) + 270, 272, (M-CO) + 242, 244. b] 8-Bromo-5-methyl-2, 3, 4, 5-tetrahydrobenzo [b] -5-tiepin-5-carbaldehyde 1.00 g (3.69 mmol) of 8-bromo-2, 3,, 5- was dissolved tetrahydrobenzo [b] tiepin-5-carbaldehyde in 8 ml of THF abs./ . r ", t. ?? r.Jhr ter-butanol abs. (10/1). At 0 ° C, 0.828 g (2 eq.) Of potassium tert-butylate was introduced, followed by the addition of 0.575 ml (2.5 eq.) Of methyl iodide after 0.25 h. Stirring was continued for 5 h at room temperature. After that, the reaction mixture was poured onto crushed ice and extracted twice with diethyl ether, the organic phase was washed with brine, dried over magnesium sulfate, filtered and finally the solvent was removed. Flash chromatography (Si02, hexane / ethyl acetate 96/4) allowed to obtain 0.6361 g of the title compound in the form of a colorless oil. i-Bromo-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepin-5-yl) -methanol 636 mg (2.23 mmol) of 8-bromo-5-methyl-2, 3 were dissolved , 5-tetrahydrobenzo [b] tiepin-5-carbaldehyde in 15 ml of abs. and cooled to 0 ° C. 84.4 mg (1 mol eq.) Of NaBH4 were introduced and the reaction was allowed to continue for 2 hours at room temperature. The pouring into crushed ice, the extraction with diethyl ether, the washing of the organic phase with water, the drying in magnesium sulfate, the filtration and the evaporation of the solvent allowed to obtain 628 mg of the title compound in the form of a. white solid, which was used in the next step without further purification (pure in 93.5% according to iGC). : rá? jLr, m? i-Bromo-5-methoxymethyl-5-methyl-2, 3,4,5-tetrahydrobenzo [b] thiepine 628 mg (2.19 mmol) of (8-bromo-5-methyl- 2, 3, 4, 5 -tetrahydrobenzo [b] thiepin-5-yl) -methanol in 12 ml of DMF abs. and treated at 0 ° C with 210 mg of NaH (ca 50% in mineral oil, ca. 2 eq.). The deprotonation was allowed to proceed at 0 ° C for 1 h. After that, the resulting solution of the corresponding sodium alkoxide was treated with 0.204 ml of methyl iodide (1.5 eq.) And kept for 2 h at room temperature. Hydrolysis with cold water, extraction with diethyl ether, washing of the organic phase with water, drying in magnesium sulfate, filtering and evaporation of the solvent allowed obtaining a crude product, which was purified by filtering in SiO2 (hexane). ethyl acetate, 96/4) to yield 576 mg of the title compound as a colorless oil (95% according to GC). MS: (M) + 300, 302, (M-CH2OCH3) + 255, 257. e] 4- (5-Methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepin-8-ylethynyl) -benzoic acid methyl ester. They were introduced at 478 mg (1.59 mmol) of 8-bromine. -5- methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepin, dissolved in 2.9 ml of piperidine, successively, 4.8 mg (0.02 eq.) Of Cul, 7.0 mg (0.02 eq. ) of Ph3P and 24.1 mg (0.01) eq.) of (Ph3P) 4Pd. After heating to 80 ° C, a solution of 508 mg (2 eq.) Of 4-ethynyl-benzoic acid methyl ester in 2.8 ml of piperidine in 2 h was introduced through a dropping funnel and then kept in this way. temperature for 3 additional hours. After cooling, the reaction mixture was poured onto crushed ice / dilute HCl, extracted with diethyl ether, the organic phase was washed with water, dried over magnesium sulfate, filtered and finally evaporated to dryness. Flash chromatography (SiO2, hexane / ethyl acetate, 95/5) allowed to obtain 270 mg of the title compound in the form of a colorless oil. MS: (M) + 380, (M-CH20CH3) 335. f] 4- (5-Methoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepin-8-ylethynyl) -benzoic acid 316 mg (0.83 mmol) of methyl ester of 4- ( 5-methoxymethyl-5-methyl-2, 3, 5-tetrahydrobenzo [b] thiepin-8-ylethynyl) -benzoic acid, in 8 ml of THF / EtOH (1/1) and treated with 1.38 ml of 3N NaOH (5 eq.). The reaction flask was kept in the dark and stirring was continued for 18 h at room temperature. After that, the mixture was poured onto crushed ice / HCl, extracted twice with diethyl ether, the organic phase was washed with brine, dried over magnesium sulfate, filtered and finally evaporated to dryness. Crystallization of the residue from hexane / ethyl acetate allowed to obtain 282 mg of the title product in the form of white crystals with a m.p. 182- 183 ° C. NMR: (1H, d, TMS, CDC13;) 1.51 (s, 3H), 1.74 (m, 1H), 1.99 (m, 1H), 2.13 (m, 2H), 2.77 (t, J = 6, 2H), 3.37 (s, 3H), 3.65 (d, J = 9, 1H), 3.95 (d, J = 9, 1H), 7.38 (s, 2H), 7.60 (d, J-8.9, 2H), 7.72 (s, 1H), 8.09 (d, J = 8.4, 2H). MS: (M) + 366, (M-CH2OCH3) + 321. 3. 2. Preparation of 4- (5-ethoxymethyl-5-methyl-2, 3, 4, 5-tetrahydrobenzo [b] tiepin-8-ylethynyl) -benzoic acid This compound was prepared in a manner analogous to that of Example 3.1, but employing in step e] 8-bromo-5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepine in . The first place of the 5-methoxymethyl derivative is. White crystals with a m.p. from 154-155 ° C. MS: (M) + 380, (M-CH2OC2H5) + 321.

Example 4 4.1. Preparation of (E) -4- (2- (5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepin-8-yl) -vinyl] -benzoic acid a] 8-Bromo-5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepine 917 mg (3.19 mmol) of (8-bromo-5-methyl 2,3,4, 5-tetrahydrobenzo [b] thiepin-5-yl) -methanol (Example 3.1.c]) in 17 ml of DMF abs. and treated at 0 ° C with 309 mg of NaH (ca 50% in mineral oil, ca. 2 eq.). The deprotonation was allowed to take place at 0 ° C for 0.25 h. After that, the resulting solution of the corresponding sodium alkoxide was treated and treated with 0.389 ml of ethyliodide (1.5 eq.) And subsequently kept for 1 h at room temperature. Hydrolysis with cold water, extraction with diethyl ether, washing of the organic phase with water, drying in magnesium sulfate, filtering and subsequent evaporation of the solvent allowed to obtain a crude product, which was purified by filtering in SiO2 ( hexane / ethyl acetate, 95/5) to yield 966 mg of the title compound in the form of a colorless oil (98% pure according to GC). b] 5-Ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepin-8-carbaldehyde 431 mg (1.37 mmol) of 8-bromo-5-ethoxymethyl-5-methyl-2 were dissolved, 3, 4, 5-tetrahydrobenzo [b] -thiepine in 3.5 ml of THF abs. and cooled to -78 ° C. 0.97 ml of n-butyllithium (1.55M, hexane) was slowly introduced and the temperature was maintained for 0.3 h. 0.316 ml (3 eq.) Of DMF abs were introduced. with a syringe and stirring was continued for 0.1 h at -78 ° C. The tempering of the reaction mixture at room temperature, the pouring into crushed ice and its extraction with diethyl ether, the washing of the organic phase with water and finally the drying in sodium sulfate, allowed to obtain, after filtering and evaporation of solvent , a crude product which was purified by flash chromatography (Si02, hexane / ethyl acetate 95/5) to obtain 0.339 g of the title compound in the form of a colorless oil (pure * É £ .á, 4 by 99% according to GC). c] (E) -4- [2- (5-Ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thio-8-yl) -vinyl] -benzoic acid methyl ester introduced 85 mg of NaH (ca. 1.4 eq., 50% in mineral oil) to a solution of 534 mg (1.4 eq.) of 4- (diethoxyphosphorylmethyl) -benzoic acid ethyl ester in 1.9 ml of DMF abs. at 0 ° C. The mixture was stirred at 0 ° C for 0.5 h and at room temperature for 1.5 h. After cooling to 0 ° C, 336 mg (1.27 mmol) of 5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepin-8-carbaldehyde, dissolved in 1 ml of DMF, was added. and the reaction was allowed to proceed for 2 h at room temperature. After that, the mixture was poured onto crushed ice, extracted twice with diethyl ether, the organic phase was washed with water, dried over magnesium sulfate, filtered and then evaporated to dryness. The purification of the residue by flash chromatography (silica gel, hexane / ethyl acetate, 95/5) allowed to obtain 409 mg of the pure, colorless title compound. d] (E) -4- [2- (5-Ethoxymethyl-5-methyl-2, 3,4,5-tetrahydrobenzo [b] thiepin-8-yl) -vinyl] -benzoic acid. 406 mg (0.99 g. mmol) of (E) -4- [2- (5-ethoxymethyl-5-methyl-2,3,3,5-tetrahydrobenzo [b] thiepin-8-yl) vinyl] -benzoic acid methyl ester at 4 ml of THF / ethanol = 1/1 and treated with 1.32 ml of 3 N NaOH (4 eq). The reaction flask was kept in the dark and stirring was continued for 18 h at room temperature. After thatThe mixture was poured onto crushed ice / dilute HCl, extracted twice with ethyl acetate, the organic phase was washed with a small amount of water, dried over magnesium sulfate, filtered and finally the solvent was evaporated. Crystallization of the residue from hexane / ethyl acetate (8/2) allowed obtaining 337 mg of the title compound in the form of white crystals with a m.p. 186-187 ° C. NMR: (1H, d, TMS, DMSO) 1.10 (t, J = 7, 3H), 1.43 (s, 3H), 1.65-2.15 (m, 9H), 2.79 (m, 2H), 3.46 (m, 2H ), 3.61 (d, J = 9, 1H), 3.88 (d, J = 9, 1H), 7.33 (s, 2H), 7.42 (d, J = 8, 1H), 7.50 (br d, J - 8) , 1H), 7.68 (br s, 1H), 7.71 (d, J = 8.3, 2H), 7.93 (d, J - 8.3, 2H), 12.92 (br s, COOH). S: (M) + 382, (M-CH2OC2H5) + 323. 4. 2. Preparation of (E) -4- [2- (5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo [b] -thym-8-yl) -vinyl] -benzoic acid IMMIGRATION & r? kii? í ?. mLnm ri.

This compound was prepared in a manner analogous to that of Example 4.1, and white crystals with a m.p. of 169-170 ° C, but using in step c] 5-methoxymethyl-5-propyl-2, 3,4, 5-tetrahydro-benzo [b] tiepin-8-carbaldehyde instead of 5-ethoxymethyl-5- methyl-2, 3, 4, 5-tetrahydrobenzo [b] tiepin-8-carbaldehyde. The first one was prepared in a manner analogous to that of Example 2.1., A] -d], but from the entire reaction sequence with 8-bromo-3,4-dihydro-2H-benzo [b] tiepin -5-ona in place of the oxa-analog. White crystals with a m.p. from 169-170 ° C. CI-MS: (M-H) + 395.

Example 5 5.1. Preparation of 4- (4-methoxymethyl-4-methyl-chroman-6-ylethyl) -benzoic acid a] 4-Methyl-chroman-4-carbaldehyde i & klá? - * - '-' «*** - - - * - < Jh, * .- yes. 5.28 g (32.55 mmol) of chroman-4-carbaldehyde were dissolved in 100 ml of abs THF. / ter-butanol abs. (5/1). At -10 ° C, 7.31 g (2 eq.) Of potassium tert-butylate were introduced, followed by the addition, after 0.25 h of 4.05 ml (2.0 eq.) Of methylodide. Stirring was continued at room temperature overnight. After that, the reaction mixture was poured into crushed ice and extracted twice with diethyl ether, the organic phase was washed with brine, dried over magnesium sulfate, filtered and finally the solvent was removed. Flash chromatography (Si02, hexane / ethyl acetate 9/1) allowed obtaining 4.29 g of the title compound in the form of a colorless oil (96.5% pure according to GC). MS: (M) + 176, (M-HCO) + 147. b] (4-Methyl-chroman-4-yl) -methanol 4.29 g (24.3 mmol) of 4-methyl-chroman-4-carbaldehyde were dissolved in 160 ml of abs. ethanol. and cooled to 0 ° C. 0.921 g (1 mol eq.) Of NaBH4 was introduced in several portions and the reaction was allowed to proceed for 16 h at room temperature. The pouring on crushed ice, the extraction - twice - with diethyl ether, the washing of the organic phase with water and the drying in magnesium sulfate allowed to obtain, after filtering and evaporation of the solvent, 4.41 g of the title compound in the shape .............., 1? J of a pale yellow oil, pure enough to pass to the next step (GC:> 97%). c] 4-Methoxymethyl-4-methyl-chroman. 2.00 g (11.2 mmol) of (4-methyl-chroman-4-yl) -methanol was dissolved in 60 ml of abs. DMF. and treated at 0 ° C with 1.08 g of NaH (ca 50% in mineral oil, ca. 2 eq.). The deprotonation was allowed to proceed at 0 ° C for 0.75 h. once hydrogen evolution ceased, the mixture was treated with 1.05 ml of methyloduro (1.5 eq.) and then kept for 0.2 h at 0 ° C and then for 0.5 h at room temperature. The careful hydrolysis with cold water, the double extraction with diethyl ether, the washing of the organic phase with water and its drying in magnesium sulphate, allowed to obtain, after filtering and evaporation of the solvent, a crude product to which it was purified by chromatography Instantaneous in SiO2, (hexane / ethyl acetate, 9/1) to obtain 2.01 g of the title compound in the form of a colorless oil (97% pure according to GC). MS: (M) + 192, (M-CH2OCH3) + 147. d] 6-Bromo-4-methoxymethyl-4-methyl-chroman. 2.00 g (10.4 mmol) of 4-methoxymethyl-4-methyl-chroman were dissolved in 25 ml of abs. CH2C12. and treated with a catalytic amount of Fe and Na2CO3 powder. After cooling to 0 ° C, 1.21 m of bromine (1.1 eq.) Was introduced and the mixture was maintained for 0.6 h at this temperature. The poured over crushed ice, extraction with diethyl ether, washing of the organic phase with water, drying in magnesium sulfate, filtering and evaporation of the solvents, and flash chromatography on Si02 (hexane / ethyl acetate 95 / 5) allowed to obtain 1676 g of the pure title compound in the form of a colorless oil (GC> 95%). MS: (M) + 270, 272, (M-CH2OCH3) + 225, 227. e] (4-Methoxymethyl-4-methyl-chroman-6-ylethynyl) -trimethylsilane To 1.67 g (6.16 mmol) of 6-bromo-4-methoxymethyl-4-methylchroman, dissolved in 11.5 ml of piperidine, were introduced in the form successive 19 mg (0.02 eq.) of Cul, 27.5 mg (0.02 eq.) of triphenylphosphine (Ph3P) and 93 mg (0.01 eq.) of (Ph3P) 4Pd. After heating to 80 ° C, a solution of 4.27 ml (5 eq.) Of trimethylsilyl-acetylene in 19 ml of piperidine was introduced in 2.5 h by means of a dropping funnel. After cooling, the reaction mixture was poured onto crushed ice, extracted with diethyl ether, the organic phase was washed with water, dried over magnesium sulfate, filtered and the solvent was evaporated. Flash chromatography (Si02, hexane / ethyl acetate 95/5) of the residue allowed 1.44 g of the title compound to be obtained in the form of a colorless oil, pure enough to pass to the next step. f] 6-Ethynyl-4-methoxymethyl-4-methyl-chroman. A catalytic amount of sodium was dissolved in 22 ml of abs. Methanol. After that, the (4-methoxymethyl-4-methyl-chroman-6-ylethynyl) -trimethylsilane which was prepared before (1.44 g, 4.99 mmol), dissolved in one portion, was added to the resulting solution of sodium methylate in one portion. small amount of methanol, at 0 ° C and subsequently maintained for 1 h at room temperature. The reaction mixture was poured onto crushed ice, extracted twice with diethyl ether, the organic phase was dried over magnesium sulfate, filtered and the solvents were removed. Flash chromatography (SiO2, hexane / ethyl acetate, 96/4) allowed to obtain 0.704 g of the title compound in the form of a pale yellow oil, pure in > 94% according to GC. MS: (M) + 216, (M-CH2OCH3) + 171. g] 4- (4-Methoxymethyl-4-methyl-chroman-6-ylethynyl) -benzoic acid methyl ester In 11 ml of DMF abs. 1061 g (1.25 eq.) of methyl 4-iodobenzoate, 114 mg (0.05 g) were dissolved in succession.

^ "* ^ I? Dh.Afc J. i eq.) Of bis (triphenylphosphine) palladium (II) chloride, 74.1 mg (0.12 eq.) Of Cul and 1.13 ml (2.5 eq.) Of triethylamine. 701 mg (3.24 mmol) of the 6-ethynyl-4-methoxymethyl-4-methyl-chroman which was prepared above, dissolved in 2.7 ml of DMF abs., Was introduced in 1 h by means of a dropping funnel. After 0.25 h, the reaction was warmed by pouring the reaction mixture onto crushed ice / HCl. Extraction with diethyl ether, washing of the organic phase twice with water, drying over magnesium sulfate, filtering and evaporation of the solvent made it possible to obtain after flash chromatography (SiO2, hexane / ethyl acetate, 92/8). 630 mg of the title compound in the form of a yellowish oil. h 4- (4-Methoxymethyl-4-mctyl-chroman-6-ylethynyl) -benzoic acid 625 mg (1.78 mmol) of 4- (4-methoxymethyl-4-methyl-chroman-6-ylethynyl) methyl ester were dissolved ) -benzoic acid in 9 ml of THF / ethanol (1/1) and treated with 2.34 ml of 3N NaOH (4 eq.). The reaction flask was kept in the dark and stirring was continued for 18 h at room temperature. After that, the mixture was poured onto crushed ice / HCl, extracted twice with diethyl ether, the organic phase was washed with water, dried over magnesium sulfate, filtered and the solvent was evaporated. The crystallization to The amount of ethyl acetate allowed 545 mg of the title product to be obtained in the form of white crystals with a mp of 202-203 ° C. NMR: (1H, d, TMS, DMSO) 1.27 (S, 3H), 1.66 (dxdxd, 1H), 2.02 (dxdxd, 1H), 3.26 (s, 3H), 3.39 (d, J = 9, 1H), 3.50 (d, J = 9, 1H), 4.19 (, 2H), 6.80 (d, J - 8.4, 1H), 7.30 (dxd, J = 8.4, J = 2, 1H), 7.57 (d, J = 2, 1H), 7.63 (d, J = 8.3, 2H), 7.95 (d, J = 8.3, 2H), 13.14 (br s, COOH) MS: (M) + 336, (M -CH2OCH3) + 291.

Example 6 6.1. Preparation of (E) -4- (4-hydroxymethyl-4-methyl-chroman-6-ylethynyl) -benzoic acid] 4-methyl-chroman-4-ylmethyl ester of acetic acid 1.00 g (5.61 mmol) was dissolved in (4-methyl-chroman-4-yl) -methanol in 6 ml of CH2C12 abs. and treated at 0 ° C with 1.17 ml (1.5 eq.) of triethylamine and 0.518 ml (1.3 eq.) of acetyl chloride and subsequently kept for 0.5 h at room temperature. The reaction mixture was poured onto crushed ice and extracted twice with diethylether.; the organic phase was washed with water, dried over sodium sulfate, filtered and finally the solvents were removed. Flash chromatography (SiO2, hexane / ethyl acetate, 9/1) allowed 1082 g of the pure title compound to be obtained in the form of a colorless oil.

MS: (M) + 220, (M-CH2OAC) + 147. b] 6-Bromo-4-methyl-chroman-4-ylmethyl ester of acetic acid Prepared in a manner analogous to that of Example 5d], by bromination of 4-methyl-chroman-4-ylmethyl ester of acetic acid which be prepared before. MS: (M) + 298, 300 (M-CH2OAc) + 225, 227. NMR: (1H, d, TMS, DMSO) 1.29 (s, 3H), 1.69 (dxdxd, 1H), 1.99 (dxdxd, 1H) , 4.08-4.2 (m, 4H), 6.73 (d, J = 8.7, 1H), 7.25 (dxd, J = 8.7, J-2.4, 1H), 7.53 (d, J = 2.4, 1H). c] 4-Methyl-6-trimethylsilanylethynyl-chroman-4-ylmethyl ester of acetic acid Prepared in a manner analogous to that of Example 5 e] from 6-bromo-4-methyl-chroman-4-ylmethyl ester of acetic acid . MS: (M) + 316 (M-CH2OAc) + 243. d] 6-ethynyl-4-methyl-l-chroman-4-ylmethyl ester of acetic acid Prepared in a manner analogous to that of Example 5f] from 4-methyl-6-tpmethyl-α-lanylethynyl-chroman-4- ilmethyl ester of acetic acid. MS: (M) + 244 (M-CH2OAc) + 171. ., ±, i. i ... e] 4- (4-Acetoxymethyl-4-methyl-chroman-6-ylethynyl) -benzoic acid methyl ester Prepared in a manner analogous to that of Example 5g] from 6-ethynyl-4-methyl-chroman 4-ylmethyl ester of acetic acid. MS: (M) + 378, (M-CH30) + 347, (M-CH2OAc) + 305. fj 4- (4-Hydroxymethyl-4-methyl-chroman-6-ylethynyl) -benzoic acid 498 mg (1.32 mmol) of 4- (4-acetoxymethyl-4-methyl-chroman-6-ylethynyl) methyl ester were dissolved. ) -benzoic acid in 7 ml of THF / ethanol (1/1) and treated with 1.75 ml of 3 N NaOH (4 eq.). The reaction mixture was kept in the dark and the stirring was continued for 4 hours at room temperature. After that, the mixture was poured into crushed ice / HCl, extracted twice with diethyl ether, the organic phase was washed with brine, dried over magnesium sulfate, filtered and then the solvent was evaporated. Crystallization from ethyl acetate at -30 ° C allowed to obtain 334 mg of the title compound in the form of ivory crystals with a m.p. of 234-235 ° C. MS: (M) + 322, (M-CH2OH) + 291. IR (cpf1): 2924, 2854, 1678, 1602, 1564, 1490, 1429, 1317, 1377, 1294, 1228, 1173, 1018, 828, 771 .

NMR: (1H, d, TMS, DMSO) 1.24 (S, 3H), 1.62 (dxdxd, 1H), 2.02 (dxdxd, 1H), 3.46 (dxd, 1H), 3.55 (dxd, 1H), 4.20 (m, 2H), 4. 91 (br t, OH), 6.79 (d, J = 8.4, 1H), 7.27 (dxd, J = 8.4, J = 2, 1H), 7.54 (d, J = 2, 1H), 7.62 (d, J - 8.3, 2H), 7.95 (d, J = 8.3, 2H), 13.15 (br s, COOH).

Example 7 Effects of selective RAR retinoids on the repair of the alveoli in emphysema induced by elastase. Selective RAR agonists were evaluated to determine the effects they exerted on alveolar repair in the elastase-induced emphysema model in rats (D. Massaro et al., Nature (Medicine, 1997, 3, 675)). These animals were divided into treatment groups of approximately eight. Pulmonary inflammation and alveolar damage were induced in male Sprague Dawley rats by a single instillation of pancreatic elastase (obtained from porcine, Calbiochem) 2 U / gram of body mass. Three weeks after the injury, all-trans retinoic acid or RAR agonist was dissolved in dimethyl sulfoxide (20 mg / ml) and stored at -20 ° C. Fresh fresh work preparations were prepared daily by dilution in PBS to a final concentration of 2 mg / ml. The animals were treated with all-trans retinoic acid (0.5 mg / kg ip) once a day through an intraperitoneal injection, beginning 21 days after the injury. The control groups were caused with elastase and, 21 days later, treated with the vehicle (DMSO / PBS) for 14 days. The animals were sacrificed 24 hours after the last dose by exsanguination under the effects of deep anesthesia. The lungs were inflated with 10% formalin subjected to neutral buffering by intratracheal instillation at a constant rate (1 ml / gram body mass / minute). An excision was made in the lung and it was immersed in fixative for 24 hours before carrying out the procedure. Standard methods were used to prepare sections of 5 μm paraffin. Sections were stained with Hematoxylin and Eosin (H% E). A computerized Morphometric analysis was carried out to determine the average alveolar size and the number of alveoli (Table 1) • Table 1 i. p. intraperitoneal p. or per os The foregoing invention has been described in some degree of detail by way of illustration and example for the purpose of providing greater clarity and understanding. It will be apparent to any person skilled in the art that changes and modifications may be made that will fall within the scope of the appended claims. Accordingly, it will be understood that the foregoing description is intended to be illustrative and not restrictive. Therefore, the scope of the invention will be determined in relation to the appended claims which are included below along with the full scope of the equivalents to which such claims are entitled. The patents, patent applications as well as the publications cited in this application are hereby incorporated by reference in their entirety for all purposes and to the same extent as if they had been denoted to each patent, patent application or publication individually. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

U?.? ^ Á ... UXÍiÍ "t

Claims (14)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of formula I characterized in that R1 is hydrogen, lower alkyl; R2 is lower alkyl; R3 is lower alkyl or H; X is oxygen or sulfur; n is 1 or 2; and where the dotted line link is optional; and the pharmaceutically active salts of the carboxylic acids of the formula I. 2. A compound according to claim 1 of formula characterized in that X, R1, R2, R3 and n are as defined according to claim 1, and the pharmaceutically active salts of the carboxylic acids of formula I. 3. The compounds according to claim 1 or 2, characterized in that X is oxygen and n is 2. 4. The compounds according to claim 3, 4- (5-methoxymethyl-5-methyl-2,3,4,5-tetrahydro-1-benzo [b] oxepin-8-yl) acid. -etinyl) -benzoic acid, 4- (5-ethoxymethyl-5-methyl-2, 3,4,5-tetrahydrobenzo [b] oxepin-8-ylethynyl) -benzoic acid, 4- (5-methyl-5-propoxymethyl) -2, 3, 4, 5- tetrahydrobenzo [b] oxepin-8-ylethynyl) -benzoic acid, (E) -4- [2- (5-methoxymethyl-5-propyl-2, 3, 4, 5-tetrahydrobenzoic acid [b] oxepin-8-yl) -vinyl] -benzoic acid, (E) -4- [2- (5-methoxymethyl-5-methyl-2, 3,4,5-tetrahydrobenzo [b] oxepin-8-) il) -vinyl] -benzoic, (E) -4- [2- (5-Methyl-5-propoxymethyl-2,3,4,5-tetrahydrobenzo [b] oxepin-8-yl) -vinyl] -benzoic acid. The compounds according to claim 1 or 2, characterized in that X is sulfur and n is 2. 6. The compounds according to claim 5, 4- (5-methoxymethyl-5-methyl-2, 3, 4 acid. , 5-tetrahydrobenzo [b] thiepin-8-ylethynyl) -benzoic acid, 4- (5-ethoxymethyl-5-methyl-2, 3,4,5-tetrahydrobenzo [b] thiepin-8-ylethynyl) -benzoic acid, acid (E) -4- [2- (5-ethoxymethyl-5-methyl-2,3,4,5-tetrahydrobenzo [b] thiepin-8-yl) -vinyl] -benzoic acid (E) -4- [ 2- (5-methoxymethyl-5-propyl-2,3,4,5-tetrahydrobenzo [b] thiepin-8-yl) -vinyl] -benzoic acid. 7. A compound according to claim 1 of the formula: characterized in that X, R1, R2, R3 and n are as defined according to claim 1, and the pharmaceutically active salts of the carboxylic acids of formula IB. .aaafe ^ ls J 8. A compound according to claim 1 0 7, characterized in that X is oxygen and n is 1. 9. The compound according to claim 8, 4- (4-methoxymethyl-4-methyl-chroman-6-ylethynyl) -benzoic acid (E) -4- acid. [2- (4-methoxymethyl-4-methyl-chroman-6-yl) -vinyl] -benzoic acid. 10. A compound according to any one of claims 1, 2 or 7, characterized in that the pharmaceutically acceptable salt of the compounds of the formula Wherein R1 is hydrogen is a salt formed from a pharmaceutically acceptable base such as, for example, the alkali, ammonium or substituted ammonium salts. 11. A compound according to any of claims 1-10, for use as a pharmaceutically active ingredient in the treatment of emphysema and associated pulmonary diseases. 12. A medicament, characterized in that it contains one or more of the compounds according to any of claims 1-10, and pharmaceutically acceptable excipients. 13. A medicament according to claim 11, for the treatment of emphysema and associated pulmonary diseases. 14. The use of a compound according to any of claims 1 to 10, for the treatment of emphysema and associated pulmonary diseases, or for the preparation of a medicament useful for the treatment of such diseases. IJ ??. A. *. A.?